The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/8/619/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 4, August 17, 1998 619-626

Articles

Antigen-dependent CD28 Signaling Selectively Enhances Survival and Proliferation in Genetically Modified Activated Human Primary T Lymphocytes

Anja Krause*, Hong-Fen Guo{ddagger}, Jean-Baptiste Latouche*, Cuiwen Tan*, Nai-Kong V. Cheung{ddagger}, and Michel Sadelain*,§

From the * Department of Human Genetics, {ddagger} Department of Pediatrics, and § Immunology Program, Memorial Sloan-Kettering Cancer Center, New York 10021

Most tumor cells function poorly as antigen-presenting cells in part because they do not express costimulatory molecules. To provide costimulation to T lymphocytes that recognize tumor cells, we constructed a CD28-like receptor specific for GD2, a ganglioside overexpressed on the surface of neuroblastoma, small-cell lung carcinoma, melanoma, and other human tumors. Recognition of GD2 was provided by a single-chain antibody derived from the GD2-specific monoclonal antibody 3G6. We demonstrate that the chimeric receptor 3G6-CD28 provides CD28 signaling upon specific recognition of the GD2 antigen on tumor cells. Human primary T lymphocytes retrovirally transduced with 3G6-CD28 secrete interleukin 2, survive proapoptotic culture conditions, and selectively undergo clonal expansion in the presence of an antiidiotypic antibody specific for 3G6-CD28. Polyclonal CD8+ lymphocytes expressing 3G6-CD28 are selectively expanded when cultured with cells expressing allogeneic major histocompatibility complex class I together with GD2. Primary T cells given such an antigen-dependent survival advantage should be very useful to augment immune responses against tumor cells.

Key Words: adoptive cell therapy • chimeric receptors • costimulation • ganglioside • gene transfer

Address correspondence to Michel Sadelain, Box 182, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: 212-639-6190; Fax: 212-717-3374; E-mail: m-sadelain @ski.mskcc.org

Abbreviations used: GAM, goat anti–mouse; GAR, goat anti– rat; LNGFR, low-affinity nerve growth factor receptor; NTP, inactive mutant form of the human LNGFR; scFv, single chain variable region fragment.


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